Polar Organometallic Reagents. Группа авторов

Scheme 1.35 Selective formation of Gilman and Lipshutz‐type cuprates from CuI.

Figure 1.24 Molecular structures of (a) Gilman amidocuprate dimer of (TMP)₂CuLi 156 and (b) Lipshutz‐type dimer of (TMP)₂Cu(I)Li₂(THF) 163.

      Source: Adapted from Komagawa et al. [221].

Readily available copper(I) halides CuCl [222] and CuBr [223] have been investigated as sources of lithium salts for Lipshutz‐type cuprates, the structures of which have been found to be very similar to that of the dimeric iodide shown in Figure 1.24. Synthetically, in situ preparations using the putative cuprate (TMP)₂Cu(Cl)Li₂164 were found to be excellent reagents for the directed cupration of heterocycles, opening up a new route to the synthesis of pharmacologically interesting azafluorenones [222].

In an attempt to decrease the costs associated with amidocuprate preparation [224], copper(I) halides have been employed extensively in the creation of DMP‐ rather than relatively expensive TMP‐cuprates (DMP = cis‐2,6‐dimethylpiperidide) [225]. The 2 : 1 reaction of amidolithium LDMP with CuX (X = Cl, Br, I) was therefore attempted as a route to more economical Lipshutz‐type cuprates. Remarkably, the formal replacement of two methyl groups from TMP with H‐atoms led to an entirely different structure‐type that could be viewed as an adduct of Gilman and Lipshutz‐type monomers (Figure 1.25 shows X = Br 165). In the pentametallic species seen, differences in Li–X (X = Cl, Br, I) and Li–N bond lengths were rationalized in terms of competing stabilization by hard/soft donors. Experiments in which TMP‐cuprates and DMP‐cuprates were both prepared in the presence of THF or Et₂O confirmed that the difference in structure‐types was attributable to the amido ligand rather than the Lewis base. Importantly, the inclusion of LiX (X = Cl, Br, I) in adduct cuprates was consistent with their observed reactivity in directed ortho‐cupration. DFT calculations reinforced this view that adducts could affect ortho‐metalation by showing that adduct cuprates represented an energetically feasible source of reactive Gilman monomers – which prior work had already suggested to represent the active species in directed ortho‐cupration [221].

The switch in structure‐type apparently enforced by the amido ligands has led to a search for other potential replacements for HTMP that might also influence structure‐type. 2‐Methylpiperidide (MP) was quickly identified as an interesting target, in view of the low cost of its conjugate acid and its chirality. The reaction of racemic LMP with CuBr in a 2 : 1 ratio yielded {(MP)₂CuLi(THF)₂}₂LiBr 166 – evidenced by X‐ray diffraction to be an adduct cuprate in the solid‐state [226]. In spite of a precedent from organocuprate chemistry [227] stereoselective assembly was not observed in this case, with X‐ray diffraction suggesting a multi‐component crystal involving permutations of R‐ and S‐MP. Meanwhile, combining the use of either DMP or MP and TMP demonstrated the ability to produce heteroleptic Lipshutz‐type structure 167. Partnering TMP with piperidide (PIP) then suggested competition between Lipshutz‐type and Gilman structures in heterodiamide chemistry by producing Gilman cuprate paddlewheel 168 ₂ (Figure 1.26).

Figure 1.25 (a) Schematic of an adduct cuprate structure‐type and (b) molecular structure of {(DMP)₂CuLi(Et₂O)}₂LiBr 165.

      Source: Adapted from Peel et al. [226].

Figure 1.26 Molecular structures of heteroleptic cuprates (a) [(TMP)(DMP)Cu(Br)Li₂(THF)₂]₂167₂ and (b) [(PIP)(TMP)CuLi]₂168₂.

      Source: Adapted from Peel et al. [226].

The structural influence of inorganic anions beyond halides capable of replacing cyanide in the creation of Lipshutz‐type cuprates was investigated through the reaction of CuSCN with an amidolithium reagent. In the event, CuSCN provided straightforward access to a range of differently solvated Lipshutz‐type cuprates (TMP)₂Cu(SCN)Li₂(L) (L = THF 169, Et₂O 170 and THP 171; THP = tetrahydropyran) when introduced to LTMP in a 1 : 2 ratio in the presence of donor solvent [228]. A strong dependence of the geometry of the solid‐state dimers of these thiocyanatocuprates on the Lewis base additives was uncovered, apparently resulting from the ability of the metallacyclic (LiSCN)₂ core to adopt boat‐like, chair‐like or planar conformations (Figure 1.27). The influence of the donor solvent was not limited to the solid‐state either: Lipshutz‐type thiocyanato(amido)cuprates were found to convert to Gilman cuprate in benzene solution, with the degree of conversion being strongly influenced by the identity of the donor solvent incorporated in the cuprate (and being most pronounced for Et₂O). In a synthetic setting, thiocyanatocuprates performed competitively with CuCl‐derived bases in the directed ortho‐cupration of halopyridines.

Cyanato(amido)cuprate analogues of the thiocyanate systems described above have also been investigated. Attempts to prepare these cuprates from the direct reaction of CuOCN with LTMP were not successful, with spectroscopy suggesting multiple products and crystallography indicating Cu/Li substitution in the solid‐state in some of these [229]. Nonetheless, Lipshutz‐type (TMP)₂Cu(OCN)Li₂(THF) 172 proved accessible by inserting LiOCN into 156 in THF. The resulting solid‐state dimer offered a geometry that differed substantially from those of the known THF‐solvated thiocyanatocuprates, but otherwise retained all the features now established to be typical for Lipshutz‐type cuprates (Figure 1.28). Curiously, when reacted with CuOCN, less sterically encumbered lithium diisopropylamide (LDA) furnished a novel amidocuprate‐amidolithium adduct (DA)₄Cu(OCN)Li₄(TMEDA)₂173, which could be viewed as arising from the attachment of units of LDA(TMEDA) to a Lipshutz‐type monomer. Meanwhile, spectroscopic investigations on CuOCN/LTMP reaction mixtures suggested the production of a new amidocopper‐amidolithium aggregate (CuTMP)₂(LTMP)₂174 (Figure 1.29) – a structural isomer of previously reported Gilman dimer [(TMP)₂CuLi]₂156 ₂ (Figure 1.24a). The reactivity of the Gilman dimer was previously established to be low. However, the knowledge that monomeric Gilman amidocuprates are reactive led to an interest in the solution behaviour and reactivity of this new adduct.